Despite an alarming increase in the burden of obesity worldwide, body adiposity seems to be a regulated physiological variable. Regulation of adiposity occurs through a classical endocrine feedback loop, in which the pancreatic beta-cell-derived hormone insulin and the adipocyte-derived hormone leptin signal the status of body energy stores to the hypothalamus. Recent advances in our understanding of the signal transduction mechanisms used by insulin and leptin in the hypothalamus to modulate neuronal firing suggest that intracellular cross-talk occurs at several levels and is a potentially important determinant of regulated body weight. These pathways are thus an attractive target for pharmacological intervention in the treatment of obesity.